Mixture for transdermal delivery of low and high molecular weight compounds

ABSTRACT

The present invention relates to the discovery of a transdermal delivery system that can deliver high molecular weight pharmaceuticals and cosmetic agents to skin cells. A novel transdermal delivery system with therapeutic and cosmetic application and methods of use of the foregoing is disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to and is acontinuation of U.S. application Ser. No. 10/183,764, filed Jun. 25,2002, which is a continuation of U.S. application Ser. No. 09/350,043,filed Jul. 8, 1999, which claims the benefit of priority to U.S.Provisional Application No. 60/092,061, filed on Jul. 8, 1998. U.S.application Ser. No. 10/183,764, U.S. application Ser. No. 09/350,043,and U.S. Provisional Application No. 60/092,061 are all hereby expresslyincorporated by reference in their entireties.

FIELD OF THE INVENTION

[0002] The present invention relates to the discovery of a transdermaldelivery system that can deliver high molecular weight pharmaceuticalsand cosmetic agents to skin cells. A novel transdermal delivery systemwith therapeutic and cosmetic application and methods of use of theforegoing is disclosed.

BACKGROUND OF THE INVENTION

[0003] The skin provides a protective barrier against foreign materialsand infection. In mammals this is accomplished by forming a highlyinsoluble protein and lipid structure on the surface of the comeocytestermed the comified envelope (CE). (Downing et al., Dermatology inGeneral Medicine, Fitzpatrick, et al., eds., pp. 210-221 (1993), Ponec,M., The Keratinocyte Handbook, Leigh, et al., eds., pp. 351-363 (1994)).The CE is composed of polar lipids, such as ceramides, sterols, andfatty acids, and a complicated network of cross-linked proteins;however, the cytoplasm of stratum comeum cells remains polar andaqueous. The CE is extremely thin (10 microns) but provides asubstantial barrier. Because of the accessibility and large area of theskin, it has long been considered a promising route for theadministration of drugs, whether dermal, regional, or systemic effectsare desired.

[0004] A topical route of drug administration is sometimes desirablebecause the risks and inconvenience of parenteral treatment can beavoided; the variable absorption and metabolism associated with oraltreatment can be circumvented; drug administration can be continuous,thereby permitting the use of pharmacologically active agents with shortbiological half-lives; the gastrointestinal irritation associated withmany compounds can be avoided; and cutaneous manifestations of diseasescan be treated more effectively than by systemic approaches. Mosttransdermal delivery systems achieve epidermal penetration by using askin penetration enhancing vehicle. Such compounds or mixtures ofcompounds are known in the art as “penetration enhancers” or “skinenhancers”. While many of the skin enhancers in the literature enhancetransdermal absorption, several possess certain drawbacks in that (i)some are regarded as toxic; (ii) some irritate the skin; (iii) some onprolonged use have a thinning effect on the skin; (iv) some change theintactness of the skin structure, resulting in a change in thediffusability of the drug; and (v) all are incapable of delivering highmolecular weight pharmaceuticals and cosmetic agents. Clearly thereremains a need for safe and effective transdermal delivery systems thatcan administer a wide-range of pharmaceuticals and cosmetic agents toskin cells.

BRIEF SUMMARY OF THE INVENTION

[0005] In aspects of the invention described below, transdermal deliverysystems are provided that can be used to administer pharmaceuticals andcosmetic agents of various molecular weights. In several embodiments,the transdermal delivery system comprises a novel formulation ofpenetration enhancer and aqueous adjuvant that enables the delivery of awide range of pharmaceuticals and cosmetic agents having molecularweights of less than 100 daltons to greater than 500,000 daltons. Forexample, embodiments of the transdermal delivery system described hereincan be used to deliver a therapeutically effective amount of anon-steroidal anti-inflammatory drug (NSAID), a capsaicin or Boswellincontaining pain-relief solution, or several different collagenpreparations. Methods of making and using the transdermal deliverydevices of the invention for the treatment and prevention of humandisease and cosmetic condition are also provided.

[0006] Accordingly, in one embodiment a transdermal delivery system isprovided that comprises an ethoxylated lipid, an alcohol mixed with theethoxylated lipid so as to form a penetration enhancer, an aqueousadjuvant mixed with the penetration enhancer, wherein the aqueousadjuvant is a plant extract from the family of Liliaceae, and a deliveryagent mixed with the aqueous adjuvant and the penetration enhancer. Insome aspects of this embodiment, the ethoxylated lipid is a vegetable oranimal oil having at least 20 ethoxylations per molecule. In otheraspects of this embodiment, about 0.1% to 40.0% by weight or volume isethoxylated lipid. Other embodiments of the invention include thetransdermal delivery system described above wherein about 0.1% to 15% byweight or volume is alcohol or wherein about 0.1% to 85% by weight orvolume is Aloe Vera. Still more embodiments of the invention have aratio of ethoxylated lipid:alcohol:aqueous adjuvant selected from thegroup consisting of 1:1:4, 1:1:14, 3:4:3, and 1:10:25.

[0007] Desirably, the transdermal delivery systems described above havedelivery agents that are molecules having a molecular weight of lessthan 6,000 daltons. In some embodiments, the transdermal delivery systemdescribed above has a delivery agent that is one or more of thecompounds selected from the group consisting of capsaicin, Boswellin,non steroidal anti-inflammatory drug, and collagen. Preferably, however,the delivery agent is a molecule having a molecular weight of greaterthan 6,000 daltons. Additional embodiments include an apparatuscomprising a vessel joined to an applicator and the transdermal deliverysystem described above incorporated in the vessel. Applicators inembodiments of the invention can be a roll-on or a sprayer.

[0008] In another aspect, a transdermal delivery system is providedwhich comprises an ethoxylated oil, an alcohol mixed with theethoxylated oil so as to form a penetration enhancer, an Aloe extractmixed with the penetration enhancer, and a therapeutically effectiveamount of capsaicin or NSAID or both mixed with the penetration enhancerand Aloe extract. In some embodiments of this aspect, thetherapeutically effective amount of capsaicin is by weight or volume0.01% to 5.0% capsaicin or 1.0% to 13% oleoresin capsicum. In otherembodiments of this aspect, the transdermal delivery system furtherincludes by weight or volume 0.1% to 10% Boswellin. As above, anapparatus having a vessel joined to an applicator that houses thetransdermal delivery system is also an embodiment and preferredapplicators include a roll-on or a sprayer.

[0009] Several methods are also within the scope of aspects of theinvention. For example, one approach involves a method of reducing painor inflammation comprising the step of administering the transdermaldelivery system described above to a subject in need and monitoring thereduction in pain or inflammation. Additional methods of the inventioninclude approaches to treat cancer and Alzheimer's disease. For example,a method of treating or preventing cancer and Alzheimer's disease cancomprise the step of identifying a subject in need of a COX enzymeinhibitor and administering the transdermal delivery system describedabove to the subject.

[0010] In addition to the delivery of low and medium molecular weightdelivery agents, several compositions that have high molecular weightdelivery agents (e.g., collagens) and methods of use of suchcompositions are embodiments of the invention. For example, oneembodiment concerns a transdermal delivery system comprising anethoxylated oil, an alcohol mixed with the ethoxylated oil so as to forma penetration enhancer, an Aloe extract mixed with the penetrationenhancer, and a therapeutically effective amount of collagen mixed withthe penetration enhancer and Aloe extract.

[0011] In different embodiments of this transdermal delivery system, thecollagen has a molecular weight less than 6,000 daltons or greater than6,000 daltons. Thus, in certain embodiments, the collagen can have anapproximate molecular weight as low as 2,000 daltons or lower. In acertain embodiment, the molecular weight is from about 300,000 daltonsto about 500,000 daltons. Further, these transdermal delivery systemscan have a therapeutically effective amount of collagen by weight orvolume that is 0.1% to 50.0% and the collagen can be Hydrocoll EN-55when the therapeutically effective amount by weight or volume is 0.1% to50.0%; the collagen can be Solu-Coll when the therapeutically effectiveamount is 0.1% to 2.0%; and the collagen can be Plantsol when thetherapeutically effective amount by weight or volume is 0.1% to 4.0%. Asabove, an apparatus having a vessel joined to an applicator that housesthe transdermal delivery system is also an embodiment and preferredapplicators include a roll-on or a sprayer.

[0012] Methods of reducing wrinkles and delivery of high molecularweight molecules are also embodiments of the invention. For example, byone approach, a method of reducing wrinkles in the skin comprisesidentifying a subject in need of skin tone restoration, administeringthe transdermal delivery system, such as is described above, to thesubject and monitoring the restoration of skin tone. Further, methods ofmaking a transdermal delivery system are within the scope of theinvention. Accordingly, a method of making a transdermal delivery systemcan involve providing an ethoxylated oil, mixing the ethoxylated oilwith an alcohol, nonionic solubilizer, or emulsifier so as to form apenetration enhancer, mixing the penetration enhancer with an aqueousadjuvant, wherein the aqueous adjuvant is an extract from a plant of theLiliaceae family; and mixing the penetration enhancer and aqueousadjuvant with a delivery agent and thereby making the transdermaldelivery system.

[0013] In some aspects of this method, the delivery agent is selectedfrom the group consisting of capsaicin, Boswellin, non steroidalanti-inflammatory drug, and collagen. In another embodiment of thismethod, the delivery agent has a molecular weight greater than 6,000daltons. As above, an apparatus having a vessel joined to an applicatorthat houses the transdermal delivery system is also an embodiment andpreferred applicators include a roll-on or a sprayer.

DETAILED DESCRIPTION OF THE INVENTION

[0014] In the following disclosure, several transdermal delivery systemsare described that can administer an effective amount of apharmaceutical or cosmetic agent to the human body. Although embodimentsof the invention can be used to administer low or high (or both low andhigh) molecular weight pharmaceuticals and cosmetic agents, preferableembodiments include transdermal delivery systems that can administercompounds having molecular weights greater than 6,000 daltons. Oneembodiment, for example, includes a transdermal delivery system that canadminister a therapeutically effective amount of a non-steroidalanti-inflammatory drug (NSAID). Another embodiment concerns atransdermal delivery system having a novel pain-relief solution (e.g., aformulation comprising capsaicin or Boswellin or both). Another aspectof the invention involves a transdermal delivery system that canadminister a collagen preparation (e.g., soluble collagens, hydrolyzedcollagens, and plant collagens). These examples are provided todemonstrate that embodiments of the invention can be used totransdermally deliver both low and high molecular weight compounds andit should be understood that many other molecules can be effectivelydelivered to the body, using the embodiments described herein, inamounts that are, therapeutically, prophylactically, or cosmeticallybeneficial.

[0015] A transdermal delivery system has three components, a deliveryagent, a penetration enhancer, and an aqueous adjuvant. Accordingly, onecomponent of the transdermal delivery system of the invention is a“delivery agent”. A molecule or a mixture of molecules (e.g., apharmaceutical or cosmetic agent) that are delivered to the body usingan embodiment of a transdermal delivery system of the invention aretermed “delivery agents”. A delivery agent that can be administered tothe body using an embodiment of the invention can include, for example,a protein, a sugar, a nucleic acid, a chemical, or a lipid. Desirabledelivery agents include, but are not limited to, glycoproteins, enzymes,genes, drugs, and ceramides. Preferred delivery agents includecollagens, NSAIDS, capsaicin, and Boswellin. In some embodiments, atransdermal delivery system comprises a combination of theaforementioned delivery agents.

[0016] The second component of a transdermal delivery system is apenetration enhancer. Desirable penetration enhancers comprise bothhydrophobic and hydrophilic components. The “hydrophobic component”includes one or more polyether compounds. One preferred polyethercompound is an ethoxylated lipid. Although an ethoxylated lipid can becreated in many ways, a preferred approach involves the reaction ofethylene oxide with a vegetable or animal oil. The “hydrophiliccomponent” can be, for example, an alcohol, a nonionic solubilizer or anemulsifier. Suitable hydrophilic components include, but are not limitedto, ethylene glycol, propylene glycol, dimethyl sulfoxide (DMSO),dimethyl polysiloxane (DMPX), oleic acid, caprylic acid, isopropylalcohol, 1-octanol, ethanol (denatured or anhydrous), and otherpharmaceutical grade or absolute alcohols with the exception ofmethanol.

[0017] Embodiments of the invention can also comprise a third componenttermed an “aqueous adjuvant”. Aqueous adjuvants include, but are notlimited to, water (distilled, deionized, filtered, or otherwiseprepared), Aloe Vera juice, and other plant extracts. Thus, severalembodiments of the invention have a penetration enhancer that includes ahydrophobic component comprising an ethoxylated oil (e.g., castor oil,glycerol, corn oil, jojoba oil, or emu oil) and a hydrophilic componentcomprising an alcohol, a nonionic solubilizer, or an emulsifier (e.g.,isopropyl alcohol) and an aqueous adjuvant such as Aloe Vera extract.Other materials can also be components of a transdermal delivery systemof the invention including fragrance, creams, ointments, colorings, andother compounds so long as the added component does not deleteriouslyaffect transdermal delivery of the delivery agent. Unexpectedly, it hasbeen found that compositions using extracts of plants of the Liliaceaefamily, such as Aloe Vera, provide superior benefits in transdermaldelivery of high molecular weight delivery agents, including collagenhaving an average molecular weight greater than 6,000 daltons.

[0018] In addition to the aforementioned compositions, methods of makingand using the embodiments of the invention are provided. In general, anembodiment of the invention is prepared by mixing a hydrophiliccomponent with a hydrophobic component and an aqueous adjuvant.Depending on the solubility of the delivery agent, the delivery agentcan be solubilized in either the hydrophobic, hydrophilic, or aqueousadjuvant components prior to mixing. In addition to physical mixingtechniques (e.g., magnetic stirring or rocker stirring) heat can beapplied to help coalesce the mixture. Desirably, the temperature is notraised above 40° C.

[0019] Several formulations of transdermal delivery system are withinthe scope of aspects of the invention. One formulation comprises a ratioof hydrophilic component:hydrophobic component:aqueous adjuvant of3:4:3. The amount of delivery agent that is incorporated into thepenetration enhancer depends on the compound, desired dosage, andapplication. The amount of delivery agent in a particular formulationcan be expressed in terms of percentage by weight, percentage by volume,or concentration. Several specific formulations of delivery systems areprovided in the Examples described herein.

[0020] Methods of treatment and prevention of pain, inflammation, andhuman disease are also provided. In some embodiments, a transdermaldelivery system comprising an NSAID, capsaicin, Boswellin or anycombination thereof is provided to a patient in need of treatment, suchas for relief of pain and/or inflammation. The use of transdermaldelivery systems described herein which contain extracts of theLiliaecae family, such as Aloe Vera extract, are particularly beneficialin the delivery of these delivery agents. A patient can be contactedwith the transdermal delivery system and treatment continued for a timesufficient to reduce pain or inflammation or inhibit the progress ofdisease.

[0021] Additionally, a method of reducing wrinkles and increasing skintightness and flexibility is provided. By this approach, a transdermaldelivery system comprising a collagen delivery agent is provided to apatient in need, the patient is contacted with the transdermal deliverysystem, and treatment is continued for a time sufficient to restore adesired skin tone (e.g., reduce wrinkles or restore skin tightness andflexibility). The transdermal delivery system described herein providesunexpectedly superior results in the delivery of collagen of allmolecular weights.

[0022] In the disclosure below, there is provided a description ofseveral of the delivery agents that can be incorporated into thetransdermal delivery devices of the present invention.

[0023] Delivery Agents

[0024] Many different delivery agents can be incorporated into thevarious transdermal delivery systems of the invention and anon-exhaustive description of embodiments is provided in this section.While the transdermal delivery of molecules having a molecular weight inthe vicinity of 6000 daltons has been reported, it has not beenpossible, until the present invention, to administer molecules ofgreater size transdermally. (U.S. Pat. No. 5,614,212 to D'Angelo etal.).

[0025] The described embodiments can be organized according to theirability to deliver a low or high molecular weight delivery agent. Lowmolecular weight molecules (e.g., a molecule having a molecular weightless than 6,000 daltons) can be effectively delivered using anembodiment of the invention and high molecular weight molecules (e.g., amolecule having a molecular weight greater than 6,000 daltons) can beeffectively delivered using an embodiment of the invention. Desirably adelivery system of the invention can administer a therapeutically orcosmetically beneficial amount of a delivery agent having a molecularweight of 50 daltons to less than 6,000 daltons. Preferably, however, adelivery system of the invention can administer a therapeutically orcosmetically beneficial amount of a delivery agent having a molecularweight of 50 daltons to 2,000,000 daltons or less. That is, a preferreddelivery system of the invention can administer a delivery agent havinga molecular weight of less than or equal to 50, 100, 200, 500, 1,000,1,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000,7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000,16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000,25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000,34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000,43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 51,000,52,000, 53,000, 54,000, 55,000, 56,000, 57,000, 58,000, 59,000, 60,000,61,000, 62,000, 63,000, 64,000, 65,000, 66,000, 67,000, 68,000, 69,000,70,000, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 125,000,150,000, 175,000, 200,000, 225,000, 250,000, 275,000, 300,000, 350,000,400,000, 450,000, 500,000, 600,000, 700,000, 800,000, 900,000,1,000,000, 1,500,000, 1,750,000, and 2,000,000 daltons.

[0026] In one aspect, a low molecular weight compound (e.g., a painrelieving substance or mixture of pain relieving substances) istransdermally delivered to cells of the body using an embodiment of atransdermal delivery system of the invention. The delivery agent can be,for example, any one or more of a number of compounds, includingnon-steroidal anti-inflammatory drugs (NSAIDs) that are frequentlyadministered systemically. These include ibuprofen(2-(isobutylphenyl)-propionic acid); methotrexate(N-[4-(2,4diamino6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamicacid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine(2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen(2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (−));phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione);sulindac-(2)-5-fuoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene-]-1H-indene-3-aceticacid; diflunisal (2′,4′, -difluoro-4-hydroxy-3-biphenylcarboxylic acid;piroxicam(4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-2-carboxamide1,1-dioxide, an oxicam; indomethacin(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-H-indole-3-acetic acid);meclofenamate sodium (N-(2,6-dichloro-m-tolyl) anthranilic acid, sodiumsalt, monohydrate); ketoprofen (2-(3-benzoylphenyl)-propionic acid;tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl-1H-pyrrole-2-acetatedihydrate); diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneaticacid, monosodium salt); hydroxychloroquine sulphate(2-{[4-[(7-chloro-4-quinolyl) amino]pentyl]ethylamino}ethanol sulfate(1:1); penicillamine (3-mercapto-D-valine); flurbiprofen([1,1-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (+−)); cetodolac(1-8- diethyl-13,4,9, tetra hydropyrano-[3-4-13]indole-1-acetic acid;mefenamic acid (N-(2,3-xylyl)anthranilic acid; and diphenhydraminehydrochloride (2-diphenyl methoxy-N, N-di-methylethamine hydrochloride).

[0027] The delivery systems of the invention having NSAIDs desirablycomprise an amount of the compound that is therapeutically beneficialfor the treatment or prevention of disease or inflammation. Severalstudies have determined an appropriate dose of an NSAID for a giventreatment or condition. (See e.g., Woodin, RN, August: 26-33 (1993) andAmadio et al., Postgrduate Medicine, 93(4):73-97 (1993)). The maximumrecommended daily dose for several NSAIDs is listed in Table 1. Theamount of NSAID recommended in the literature and shown in Table 1 canbe incorporated into a delivery system of the invention. Because thetransdermal delivery system of the invention can administer a deliveryagent in a site-specific manner, it is believed that a lower total doseof therapeutic agent, as compared to the amounts provided systemically,will provide therapeutic benefit. Additionally, greater therapeuticbenefit can be gained by using a transdermal delivery system of theinvention because a high dose of therapeutic agent (e.g., an NSAID) canbe applied to the particular site of inflammation. That is, in contrastto systemic administration, which applies the same concentration oftherapeutic to all regions of the body, a transdermal delivery system ofthe invention can site-specifically administer a therapeutic and,thereby, provides a much greater regional concentration of the agentthan if the same amount of therapeutic were administered systemically.TABLE 1 Maximum Recommended Agent Daily Dose Indomethacin 100 mgIbuprofen 3200 mg  Naproxen 1250 mg  Fenoprofen 3200 mg  Tolmetin 2000mg  Sulindac 400 mg Meclofenamate 400 mg Ketoprofen 300 mg Proxicam  10mg Flurbiprofen 300 mg Diclofenac 200 mg

[0028] Additionally, desirable embodiments include a delivery systemthat can administer a pain relieving mixture comprising capsaicin (e.g.,oleoresin capsicum) or Boswellin or both. Capsaicin(8-methyl-N-vanillyl-6-nonenamide), the pungent component of paprika andpeppers, is a potent analgesic. (See U.S. Pat. No. 5,318,960 to Toppo,U.S. Pat. No. 5,885,597 to Botknecht et al., and U.S. Pat. No. 5,665,378to Davis et al.). Capsaicin produces a level of analgesia comparable tomorphine, yet it is not antagonized by classical narcotic antagonistssuch as naloxone. Further, it effectively prevents the development ofcutaneous hyperalgesia, but appears to have minimal effects on normalpain responses at moderate doses. At high doses capsaicin also exertsanalgesic activity in classical models of deep pain, elevating the painthreshold above the normal value. Capsaicin can be readily obtained bythe ethanol extraction of the fruit of Capsicum frutescens or Capsicumannum. Capsaicin and analogs of capsaicin are available commerciallyfrom a variety of suppliers, and can also be prepared synthetically bypublished methods. Aspects of the invention encompass the use ofsynthetic and natural capsaicin, capsaicin derivatives, and capsaicinanalogs.

[0029] A form of capsaicin used in several desirable embodiments isoleoresin capsicum. Oleoresin capsicum contains primarily capsaicin,dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, andhomodihydrocapsaicin. The term “capsaicin” collectively refers to allforms of capsaicin, capsicum, and derivatives or modifications thereof.The pungency of these five compounds, expressed in Scoville units, areprovided in Table 2. TABLE 2 Compound Pungency × 100,000 SU Capsaicin160 Dihydrocapsaicin 160 Nordihydrocapsaicin 91 Homocapsaicin 86Homodihydrocapsaicin 86

[0030] The delivery systems of the invention having capsaicin desirablycomprise by weight or volume 0.01% to 1.0% capsaicin or 1.0% to 10%oleoresin capsicum. Preferred amounts of this delivery agent include byweight or volume 0.02% to 0.75% capsaicin or 2.0% to 7.0% oleoresincapsicum. For example, the delivery systems of the invention havingcapsaicin can comprise by weight or volume less than or equal to 0.01%,0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%,0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.15%,0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.325%, 0.35%, 0.375%, 0.4%,0.425%, 0.45%, 0.475%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%,0.85%, 0.9%, 0.95%, and 1.0% capsaicin. Although not a desirableembodiment, the delivery systems of the invention having capsaicin cancomprise an amount of capsaicin by weight or volume that is greater than1.0%, such as 1.2%, 1.5%, 1.8%, 2.0%, 2.2%, 2.5%, 2.8%, 3.0%, 3.5%,4.0%, 4.5%, and 5.0%. Similarly, the delivery systems of the inventionhaving oleoresin capsicum can comprise an amount of oleoresin capsicumless than 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%,6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 11.0%, 12.0%, and13.0%.

[0031] Boswellin, also known as Frankincense, is an herbal extract of atree of the Boswellia family. Boswellin can be obtained, for example,from Boswellia thurifera, Boswellia carteri, Boswellia sacra, andBoswellia serrata. There are many ways to extract Boswellin andBoswellin gum resin and boswellic acids are obtainable from severalcommercial suppliers (a 65% solution of Boswellic acid is obtainablefrom Nature's Plus over the internet). Some suppliers also providecreams and pills having Boswellin with and without capsaicin and otheringredients. Embodiments of the invention comprise Boswellin and theterm “Boswellin” collectively refers to Frankincense, an extract fromone or more members of the Boswellia family, Boswellic acid, syntheticBoswellin, or modified or derivatized Boswellin.

[0032] The delivery systems of the invention having Boswellin desirablycomprise 0.1% to 10% Boswellin by weight or volume. Preferred amounts ofthis delivery agent include 1.0% to 5.0% Boswellin by weight. Forexample, the delivery systems of the invention having Boswellin cancomprise by weight or volume less than or equal to 0.1%, 0.15%, 0.2%,0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%,0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%,1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.8%, 1.85%,1.9%, 1.95%, and 2.0%, 2.1%, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4%,2.45%, 2.5%, 2.55%, 2.6%, 2.65%, 2.7%, 2.75%, 2.8%, 2.85%, 2.9%, 2.95%,3.0%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%, 3.4%, 3.45%, 3.5%, 3.55%,3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%, 3.95%, 4.0%,. 4.1%, 4.15%,4.2%, 4.25%, 4.3%, 4.35%, 4.4%, 4.45%, 4.4%, 4.45%, 4.5%, 4.55%, 4.6%,4.65%, 4.7%, 4.75%, 4.8%, 4.85%, 4.9%, 4.95%, and 5.0% Boswellin.Although not a desirable embodiment, the delivery systems of theinvention having Boswellin can comprise amounts of Boswellin by weightthat are greater than 5.0%, such as 5.5%, 5.7%, 6.0%, 6.5%%, 6.7%, 7.0%,7.5%, 7.7%, 8.0%, 8.5%, 8.7%, 9.0%, 9.5%, 9.7%, and 10.0% or greaAdditionally, Boswellin from different sources can be combined tocompose the Boswellin component of an embodiment. For example, in oneembodiment an extract from Boswellia thurifera is combined with anextract from Boswellia serrata.

[0033] Additional embodiments of the invention comprise a transdermaldelivery system that can administer a pain relieving solution comprisingtwo or more members selected from the group consisting of NSAIDs,capsacin, and Boswellin. The delivery systems of the invention thatinclude two or more members selected from the group consisting ofNSAIDs, capsacin, and Boswellin desirably comprise an amount of deliveryagent that can be included in a delivery agent having an NSAID,capsaicin, or Boswellin by itself. For example, if the delivery agentcomprises an NSAID, the amount of NSAID that can be used can be anamount recommended in the literature (See e.g., Woodin, RN, August:26-33 (1993) and Amadio, et al., Postgrduate Medicine, 93(4):73-97(1993)), or an amount listed in Table 1. Similarly, if capsaicin is acomponent of the delivery agents then the delivery system can compriseby weight or volume less than or equal to 0.01%, 0.015%, 0.02%, 0.025%,0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%,0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.15%, 0.175%, 0.2%, 0.225%,0.25%, 0.275%, 0.3% 0.325%, 0.35%, 0.375%, 0.4%, 0.425%, 0.45%, 0.475%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, and1.0% capsaicin or less than 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%,4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%,11.0%, 12.0%, 13.0%, oleoresin capsicum. Further, if Boswellin is acomponent of the delivery agents, then the delivery system can compriseby weight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%,0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%,0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%,1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%,2.0%, 2.1%, 2.15%, 2.2%, 2.25%, 2.3%, 2.35%, 2.4%, 2.45%, 2.5%, 2.55%,2.6%, 2.65%, 2.7%, 2.75%, 2.8%, 2.85%, 2.9%, 2.95%, 3.0%, 3.1%, 3.15%,3.2%, 3.25%, 3.3%, 3.35%, 3.4%, 3.4%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%,3.75%, 3.8%, 3.85%, 3.9%, 3.95%, 4.0%,. 4.1%, 4.15%, 4.2%, 4.25%, 4.3%,4.35%, 4.4%, 4.45%, 4.4%, 4.45%, 4.5%, 4.55%, 4.6%, 4.65%, 4.7%, 4.75%,4.8%, 4.85%, 4.9%, 4.95%, 5.0%, 5.5%, 5.7%, 6.0%, 6.5%, 6.7%, 7.0%,7.5%, 7.7%, 8.0%, 8.5%, 8.7%, 9.0%, 9.5%, 9.7%, and 10.0% Boswell

[0034] In addition to low molecular weight delivery agents, many mediummolecular weight delivery agents (eg., humates) can be delivered tocells in the body by using an embodiment of the transdermal deliverysystem. Synthetic humates (“Hepsyls”) are medium molecular weightcompounds (1,000 to 100,000 daltons), which are known to be strongantiviral and antimicrobial medicaments (International ApplicationPublication No. WO 9834629 to Laub). Hepsyls are generally characterizedas polymeric phenolic materials comprised of conjugated aromatic systemsto which are attached hydroxyl, carboxyl, and other covalently boundfunctional groups. A delivery system that can administer Hepsyls tocells of the body has several pharmaceutical uses, including but notlimited to, treatment of topical bacterial and viral infections.

[0035] Accordingly, in another aspect of the invention, a transdermal.delivery system that can administer a medium molecular weight compound(e.g., a form of Hepsyl) to cells of the body is provided. As describedabove, many different medium molecular weight compounds can beadministered by using an embodiment of a transdermal delivery system ofthe invention and the use of a medium molecular weight Hepsyl as adelivery agent is intended to demonstrate that embodiments of theinvention can deliver many medium molecular weight compounds to calls ofthe body.

[0036] In addition to low molecular weight delivery agents and mediummolecular weight delivery agents, several high molecular weight deliveryagents (e.g., glycoproteins) can be delivered to cells in the body byusing an embodiment of the transdermal delivery system. Glycoproteinsare high molecular weight compounds, which are generally characterizedas conjugated proteins containing one or more heterosaccharides asprosthetic groups. The heterosaccharides are usually branched but have arelatively low number of sugar residues, lack a serially repeating unit,and are covalently bound to a polypeptide chain. Several forms ofglycoproteins are found in the body. For example, many membrane boundproteins are glycoproteins, the substances that fill the intercellularspaces (e.g., extracellular matrix proteins) are glycoproteins, and thecompounds that compose collagens, proteoglycans, mucopolysaccharides,glycosaminoglycans, and ground substance are glycoproteins. A deliverysystem that can administer glycoproteins to cells of the body hasseveral pharmaceutical and cosmetic uses, including but not limited to,the restoration of skin elasticity and firmness (e.g., the removal ofwrinkles by transdermal delivery of collagen) and the restoration offlexible and strong joints (e.g., water retention in joints can beincreased by transdermal delivery of proteoglycans).

[0037] Accordingly, in another aspect of the invention, a transdermaldelivery system that can administer a high molecular weight compound(e.g., a form of collagen) to cells of the body is provided. Asdescribed above, many different high molecular weight compounds can beadministered by using an embodiment of a transdermal delivery system ofthe invention and the use of a high molecular weight collagen as adelivery agent is intended to demonstrate that embodiments of theinvention can deliver many high molecular weight compounds to cells ofthe body.

[0038] Collagens exist in many forms and can be isolated from a numberof sources. Additionally, several forms of collagen can be obtainedcommercially (e.g., Brooks Industries Inc., New Jersey). Many lowmolecular weight collagens can be made, for example, by hydrolysis.Several transdermal delivery systems of the invention can delivercollagens having molecular weights below 6,000 daltons. Additionally,several high molecular weight collagens exist. Some are isolated fromanimal or plant sources and some are synthesized or produced throughtechniques common in molecular biology. Several transdermal deliverysystems of the invention can deliver collagens having molecular weightsof 1,000 daltons to greater than 2,000,000 daltons. That is, embodimentsof the transdermal delivery systems can deliver collagens havingmolecular weights of less than or equal to 1,000, 1,500, 2,000, 2,500,3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 7,000, 8,000, 9,000,10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000,19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000,28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000,37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000,46,000, 47,000, 48,000, 49,000, 50,000, 51,000, 52,000, 53,000, 54,000,55,000, 56,000, 57,000, 58,000, 59,000, 60,000, 61,000, 62,000, 63,000,64,000, 65,000, 66,000, 67,000, 68,000, 69,000, 70,000, 75,000, 80,000,85,000, 90,000, 95,000, 100,000, 125,000, 150,000, 175,000, 200,000,225,000, 250,000, 275,000, 300,000, 350,000, 400,000, 450,000, 500,000,600,000, 700,000, 800,000, 900,000, 1,000,000, 1,500,000, 1,750,000, and2,000,000 daltons.

[0039] In some embodiments, the commercially available collagen“Hydrocoll EN-55” was provided as the delivery agent and was deliveredto cells of a test subject. This form of collagen is hydrolyzed collagenand has a molecular weight of 2,000 daltons. In another embodiment, thecommercially available collagen “Solu-Coll” was provided as the deliveryagent and was delivered to cells of a test subject. This form ofcollagen is a soluble collagen having a molecular weight of 300,000daltons. An additional embodiment includes the commercially availablecollagen “Plantsol”, which is obtained from yeast and has a molecularweight of 500,000 daltons. This collagen was also provided as a deliveryagent and was delivered to cells of a test subject.

[0040] The delivery systems of the invention having a form of collagenas a delivery agent desirably comprise by weight or volume between 0.1%to 50.0% collagen depending on the type of collagen, its solubility, andthe intended application. That is, some transdermal delivery systems ofthe invention comprise by weight or volume less than or equal to 0.1%,0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%,0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%,2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%,5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%,7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%,10.5%, 10.75%, 11.0%,. 11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%,12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%,15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%,20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%,25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%,30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%,35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%,40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, or50.0% collagen.

[0041] For example, embodiments having Hydrocoll-EN55 can comprise byweight or volume less than or equal to 1.0%, 1.25%, 1.5%, 1.75%, 2.0%,2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%,5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%,7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%,10.5%, 10.75%, 11.0%,. 11.25% 11.5%, 11.75%, 12.0%, 12.25%, 12.5%,12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%,15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%,20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%,25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%,30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%,35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%,40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, or50.0% Hydrocoll-EN-55. Further, delivery systems of the invention havingSolu-Coll can comprise by weight or volume less than or equal to 0.1%,0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%,0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.15%, 1.2%, 1.25%,1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%,1.85%, 1.9%, 1.95%, or 2.0% Solu-Coll. Additionally, delivery systems ofthe invention having Plantsol can comprise by weight or volume less thanor equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%,0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%,1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%,1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2.0%, 2.1%, 2.15%, 2.2%, 2.25%,2.3%, 2.35%, 2.4%, 2.45%, 2.5%, 2.55%, 2.6%, 2.65%, 2.7%, 2.75%, 2.8%,2.8%, 2.9%, 2.95%, 3.0%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%, 3.4%,3.45%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%, 3.95%,or 4.0% Plantsol.

[0042] In other embodiments of the invention, a transdermal deliverysystem that can administer a collagen solution comprising two or moreforms of collagen (e.g., Hydro-Coll EN-55, Solu-coll, or Plantsol) isprovided. The delivery systems of the invention that include two or moreforms of collagen desirably comprise an amount of delivery agent thatcan be included in a delivery agent having the specific type of collagenby itself. For example, if the mixture of delivery agents comprisesHydro-Coll EN55, the amount of Hydro-Coll EN55 in the transdermaldelivery system can comprise by weight or volume less than or equal to1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%,3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%,6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%,9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%,11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%,14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%,18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%,23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%,28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%,33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%,38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 41.0%, 42.0%, 43.0%, 44.0%, 45.0%,46.0%, 47.0%, 48.0%, 49.0%, or 50.0% Hydrocoll-EN-55. Similarly if themixture of delivery agents have Solu-coll, then the amount of Solu-collin the delivery device can comprise by weight or volume less than orequal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%,0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%,1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%,1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, or 2.0% or Solu-Coll. Further, ifthe mixture of delivery agents have Plantsol, then the amount ofPlantsol in the delivery system can comprise by weight or volume lessthan or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%,1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%,1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2.0%, 2.1%, 2.15%, 2.2%,2.25%, 2.3%, 2.35%, 2.4%, 2.45%, 2.5%, 2.55%, 2.6%, 2.65%, 2.7%, 2.75%,2.8%, 2.85%, 2.9%, 2.95%, 3.0%, 3.1%, 3.15%, 3.2%, 3.25%, 3.3%, 3.35%,3.4%, 3.45%, 3.5%, 3.55%, 3.6%, 3.65%, 3.7%, 3.75%, 3.8%, 3.85%, 3.9%,3.95%, or 4.0% Plantsol.

[0043] In the section below, there is a description of the manufactureand use of a penetration enhancer that enables the delivery of both lowand high molecular weight molecules to the skin cells of the body.

[0044] Penetration Enhancers

[0045] A penetration enhancer included in many embodiments of theinvention is comprised of two components—a hydrophobic component and ahydrophilic component. Desirably, the hydrophobic component comprises apolyether compound, such as an ethoxylated vegetable or animal oil, thathas the ability to reduce the surface tension of materials that aredissolved into it. Preferable ethoxylated oils can be obtained orcreated from, for example, castor oil, jojoba oil, corn oil, and emuoil. Desirably, the ethoxylated compound comprises at least 20-25ethoxylations per molecule and preferably the ethoxylated compoundcomprises at least 30-35 ethoxylations per molecule. Thus, in apreferred embodiment, an ethoxylated oil comprises a molar ratio ofethylene oxide:oil of 35:1. A 99% pure ethylene oxide/castor oil havingsuch characteristics can be obtained commercially (BASF) or such anethoxylated compound can be synthesized using conventional techniques.Desirable compounds often found in ethoxylated oils that are beneficialfor some embodiments and methods of the invention areglycerol-polyethylene glycol ricinoleate, the fatty esters ofpolyethylene glycol, polyethylene glycol, and ethoxylated glycerol. Someof these desirable compounds exhibit hydrophilic properties and thehydrophilic-lipophilic balance (HLB) is preferably maintained between 10and 18. In some embodiments, more than one ethoxylated compound is addedor another hydrophobic compound is added (e.g., Y-Ling-Y-Lang oil; YoungLiving Essential Oils, Lehl, Utah)) to balance or enhance thepenetration enhancer.

[0046] Depending on the type of delivery agent and the intendedapplication, the amount of ethoxylated lipid(s) in the delivery systemcan vary. For example, delivery systems of the invention can comprisebetween 0.1% and 40% by weight or volume ethoxylated compound(s). Thatis, embodiments of the invention can comprise by weight or volume lessthan or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%,1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.7%,4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%,6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%,9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%, 11.25%, 11.5%, 11.75%,12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%, 14.0%,14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%,18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%, 23.0%,23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%, 28.0%,28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%, 33.0%,33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%, 38.0%,38.5%, 39.0%, 39.5%, and 40.0% ethoxylated lipid(s).

[0047] The hydrophilic component of the penetration enhancers of theinvention desirably comprise an alcohol, a non-ionic solubilizer, or anemulsifier. Compounds such as ethylene glycol, propylene glycol,dimethyl sulfoxide (DMSO), dimethyl polysiloxane (DMPX), oleic acid,caprylic acid, isopropyl alcohol, 1-octanol, ethanol (denatured oranhydrous), and other pharmaceutical grade or absolute alcohols with theexception of methanol can be used. Preferred embodiments comprise analcohol (e.g., absolute isopropyl alcohol), which is commerciallyavailable. As above, the amount of hydrophilic component in thepenetration enhancer depends on the type of the delivery agent and theintended application. The hydrophilic component of a penetrationenhancer of the invention can comprise between 0.1% and 50% by weight orvolume. That is, a delivery system of the invention can comprise byweight or volume less than or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%,0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%,0.9%, 0.95%, 1.0%, 1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%,3.25%, 3.5%, 3.75%, 4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%,6.0%, 6.25%, 6.5%, 6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%,8.75%, 9.0%, 9.25%, 9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,.11.25%, 11.5%, 11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%,13.5%, 13.75%, 14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%,17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%,22.0%, 22.5%, 23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%,27.0%, 27.5%, 28.0%, 28.5%, 29.0%, 29.5%, 30.0%, 30.5%, 31.0%, 31.5%,32.0%, 32.5%, 33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%,37.0%, 37.5%, 38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 41.0%, 42.0%, 43.0%,44.0%, 45.0%, 46.0%, 47.0%, 48.0%, 49.0%, or 50.0% hydrophiliccomponent.

[0048] In addition to the delivery agent and penetration enhancer,desirable transdermal delivery devices comprise a third component—anaqueous adjuvant. In the section below, there is described themanufacture and use of a preferred aqueous adjuvant, Aloe Vera, thatenhances the delivery of both low and high molecular weight molecules tothe skin cells of the body.

[0049] Aqueous Adjuvants

[0050] The term “Aloe” refers to the genus of South African plants ofthe Liliaceae family, of which the Aloe barbadensis plant is a species.Aloe is an intricate plant, which contains many biologically activesubstances. (Cohen, et al. in Wound Healing/Biochemical and ClinicalAspects, 1st ed. W B Saunders, Philadelphia (1992)). Over 300 species ofAloe are known, most of which are indigenous to Africa. Studies haveshown that the biologically active substances are located in threeseparate sections of the Aloe leaf—a clear gel fillet located in thecenter of the leaf, in the leaf rind or cortex of the leaf and in ayellow fluid contained in the pericyclic cells of the vascular bundles,located between the leaf rind and the internal gel fillet, referred toas the latex. Historically, Aloe products have been used indermatological applications for the treatment of burns, sores and otherwounds. These uses have stimulated a great deal of research inidentifying compounds from Aloe plants that have clinical activity,especially anti-inflammatory activity. (See, e.g., Grindlay and Reynolds(1986) J. of Ethnopharmacology 16:117-151; Hart, et al. (1988) J. ofEthnopharmacology 23:61-71). As a result of these studies there havebeen numerous reports of Aloe compounds having diverse biologicalactivities, including anti-tumor activity, anti-gastric ulcer,anti-diabetic, anti-tyrosinase activity, (See e.g., Yagi, et al. (1977)Z. Naturforsch. 32c:731-734), and antioxidant activity (InternationalApplication Serial No. PCT/US95/07404). Recent research has also shownthat Aloe Vera, a term used to describe the extract obtained fromprocessing the entire leaf, isolated from the Aloe Vera species of Aloe,can be used as a vehicle for delivering hydrocortisone, estradiol, andtestosterone propionate. (Davis, et al, JAPMA 81:1 (1991) and U.S. Pat.No. 5,708,038 to Davis)). As set forth in Davis (U.S. Pat. No.5,708,308), one embodiment of “Aloe Vera” can be prepared by “whole-leafprocessing” of the whole leaf of the Aloe barbadensis plant. Briefly,whole leaves obtained from the Aloe barbadensis plant are ground,filtered, treated with cellulase (optional) and activated carbon andlyophilized. The lyophilized powder is then reconstituted with waterprior to use.

[0051] In some embodiments, Aloe Vera is commercially available andobtained through Aloe Laboratories. In some embodiments, the Aloe Verais manufactured by manually harvesting the Aloe leaves. Next, the leavesare washed with water and the thorns on both ends are cut. The leavesare then hand-filleted so as to extract the inner part of the leaf. Theinner gel is passed through a grinder and separator to remove fiber fromthe gel. Next, the gel is put into a pasteurizing tank where L-AscorbicAcid (Vitamin C) and preservatives are added. The gel is pasteurized at85° C. for 30 minutes. After pasteurization, the gel is put into aholding tank for about one or two days, after which the gel is sentthrough a ½ micron filter. Finally, the gel is cooled down through aheat exchanger and stored in a steamed, sanitized and clean 55 gallondrum.

[0052] The above described sources and manufacturing methods of AloeVera are given as examples and not intended to limit the scope of theinvention. One of ordinary skill in the art will recognize that AloeVera is a well known term of art, and that Aloe Vera is available fromvarious sources and manufactured according to various methods.

[0053] Several embodiments of the invention are comprised of aqueousadjuvants such as Aloe Vera juice or water or both. Absolute Aloe Vera(100% pure) can be obtained from commercial suppliers (Lily of theDesert, Irving, Tex.). Aloe Vera juice, prepared from gel fillet, has anapproximate molecular weight of 200,000 to 1,400,000 daltons. Whole leafAloe Vera gel has a molecular weight of 200,000 to 3,000,000 dependingon the purity of the preparation. Although, preferably, the embodimentsof the invention having Aloe Vera comprise Aloe Vera juice, otherextracts from a member of the Liliaceae family can be used (e.g., anextract from another Aloe species).

[0054] Transdermal delivery systems of the invention having Aloe Veracan comprise between 0.1% to 85.0% by weight or volume Aloe Vera. Thatis, embodiments of the invention can comprise by weight or volume lessthan or equal to 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%,1.25%, 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%,4.0%,. 4.25%, 4.5%, 4.75%, 5.0%, 5.25%, 5.5%, 5.75%, 6.0%, 6.25%, 6.5%,6.75%, 7.0%, 7.25%, 7.5%, 7.75%, 8.0% 8.25%, 8.5%, 8.75%, 9.0%, 9.25%,9.5%, 9.75%, 10.0%, 10.25%, 10.5%, 10.75%, 11.0%,. 11.25%, 11.5%,11.75%, 12.0%, 12.25%, 12.5%, 12.75%, 13.0%, 13.25%, 13.5%, 13.75%,14.0%, 14.25%, 14.5%, 14.75%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%,18.0%, 18.5% 19.0%, 19.5%, 20.0%, 20.5%, 21.0%, 21.5%, 22.0%, 22.5%,23.0%, 23.5%, 24.0%, 24.5%, 25.0%, 25.5%, 26.0%, 26.5%, 27.0%, 27.5%,28.0%, 28.5%, 29.0%, 29.5% 30.0%, 30.5%, 31.0%, 31.5%, 32.0%, 32.5%,33.0%, 33.5%, 34.0%, 34.5%, 35.0%, 35.5%, 36.0%, 36.5%, 37.0%, 37.5%,38.0%, 38.5%, 39.0%, 39.5%, 40.0%, 40.25%, 40.5%, 40.75%, 41.0%, 41.25%,41.5%, 41.75%, 42.0%, 42.25%, 42.5%, 42.75%, 43.0%, 43.25%, 43.5%,43.75%, 44.0%, 44.25%, 44.5%, 44.75%, 45.0%, 45.25%, 45.5%, 45.75%,46.0%, 46.25%, 46.5%, 46.75%, 47.0% 47.25%, 47.5%, 47.75%, 48.0%,48.25%, 48.5%, 48.75%, 49.0%, 49.25%, 49.5%, 49.75%, 50.0%,. 50.25%,50.5%, 50.75%, 51.0%, 51.25%, 51.5%, 51.75%, 52.0%, 52.25%, 52.5%,52.75%, 53.0%, 53.25%, 53.5%, 53.75%, 54.0%, 54.5%, 54.0%, 54.5%, 55.0%,55.5%, 56.0% 56.5%, 57.0%, 57.5%, 58.0%, 58.5%, 59.0%, 59.5%, 60.0%,60.5%, 61.0%, 61.5%, 62.0%, 62.5%, 63.0%, 63.5%, 64.0%, 64.5%, 65.0%,65.5%, 66.0%, 66.5%, 67.0%, 67.5%, 68.0%, 68.5%, 69.0%, 69.5%, 70.0%,70.5%, 71.0%, 71.5%, 72.0%, 72.5%, 73.0%, 73.5%, 74.0%, 74.5%, 75.0%,75.5%, 76.0%, 76.5%, 77.0%, 77.5%, 78.0%, 78.5%, 79.0%, 79.5%, 80.0%,80.5%, 81%, 81.5%, 82%, 82.5%, 83%, 83.5%, 84%, 84.5%, and 85% AloeVera.

[0055] The amount of water in the delivery system generally depends onthe amount of other reagents (e.g., delivery agent, penetrationenhancer, and other aqueous adjuvants or fillers). Although water isused as the sole aqueous adjuvant in some embodiments, preferredembodiments use enough water to make the total volume of a particularpreparation of a delivery system such that the desired concentrations ofreagents in the penetration enhancer, aqueous adjuvant, and deliveryagent are achieved. Suitable forms of water are deionized, distilled,filtered or otherwise purified. Clearly, however, any form of water canbe used as an aqueous adjuvant.

[0056] In addition to the aforementioned compositions, methods of makingand using the transdermal delivery systems of the invention are providedbelow.

[0057] Preparing Transdermal Delivery Systems

[0058] In general, an embodiment of the invention is prepared bycombining a penetration enhancer with an aqueous adjuvant and a deliveryagent. Depending on the solubility of the delivery agent, the deliveryagent can be solubilized in either the hydrophobic or hydrophiliccomponents of the penetration enhancer. Additionally, some deliveryagents can be solubilized in the aqueous adjuvant prior to mixing withthe penetration enhancer. Desirably, the pH of the mixture is maintainedbetween 3 and 11 and preferably between 5 and 9. That is, duringpreparation and after preparation the pH of the solution is desirablymaintained at less than or equal to 3.0, 3.25, 3.5, 3.75, 4.0, 4.25,4.5, 4.75, 5.0, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7.0, 7.25, 7.5,7.75, 8.0, 8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75, 10.0, 10.25, 10.5,10.75, or 11.0. Several physical mixing techniques can be employed tohelp the delivery system coalesce. For example, a magnetic stir plateand bar can be used, however, the speed of stirring is preferablyminimized so as not to drive air into the mixture. Additionally, arocker can be used to bring components of the delivery system together.Heat can also be applied to help coalesce the mixture but desirably, thetemperature is not raised above 40° C. so that labile aqueous adjuvantsor labile delivery agents are not degraded. Preferably, once thedelivery system has coalesced, other components such as fragrances andcolors are added or the delivery system is incorporated into a cream orointment or a device for applying the delivery system.

[0059] Several formulations of delivery system are within the scope ofaspects of the invention. Desirably, the ratio of hydrophiliccomponent:hydrophobic component:aqueous adjuvant is 3:4:3, but preferredformulations comprise 1:1:4, 1:1:14, and 1:10:25. As described above, asufficient amount of delivery agent to suit the intended purpose isincorporated into the delivery system. The amount of delivery agent thatis incorporated into the penetration enhancer depends on the compound,desired dosage, and application.

[0060] Typically, a preferable transdermal delivery system is made byproviding an ethoxylated oil, mixing the ethoxylated oil with analcohol, non-ionic solubilizer, or emulsifier so as to form apenetration enhancer, mixing the penetration enhancer with an aqueousadjuvant (e.g., an extract from a plant of the Liliaeacae family), andmixing the penetration enhancer and aqueous adjuvant with a deliveryagent and thereby making the transdermal delivery system. For example,an embodiment of a transdermal delivery system comprising a pain reliefsolution is manufactured as follows. A solution of 2.0% to 7.0%oleoresin capsicum, 2.5 grams of Boswellin, and 1.5 mls of a 65%solution of Frankensence is mixed with 400 ml of absolute carpilicalcohol or isopropyl alcohol, 300 ml of ethylene oxide admixed andreacted with castor oil, and 300 ml of a 100% solution of Aloe Vera.This transdermal delivery system has been observed to alleviate painwhen rubbed on a targeted area.

[0061] The delivery systems of the invention having a form of Hepsyl asa delivery agent desirably are comprised by weight or volume of between0.005% to 12.0% Hepsyl, depending on the type of Hepsyl, its solubility,and the intended application. For example, embodiments having Hepsyl CA1501C. Hepsyl CGA 1501K., and Hepsyl RA 150K can be comprised by weightor volume of 0.01-2 grams of Hepsyl delivery agent, 0-50 mL ofhydrophobic penetration enhancers (e.g., ethoxylated castor oil, jojobaoil, etc.), 0-50 mL of hydrophilic penetration enhancers, nonionicsolubilizers, or emulsifiers (e.g., isopropyl. alcohol, DMSO, etc.), and0-50 mL of aqueous adjuvant (e.g., water, Aloe Vera extract, etc.). Aparticularly desirable embodiment of the invention is comprised of0.1-0.5 gram of Hepsyl, 5-10 mL of ethoxylated castor oil, 5-10 mL ofisopropyl alcohol, and 5-10 mL of Aloe Vera extract. By using theseformulations, other delivery agents can be incorporated into atransdermal delivery system. Formulations of transdermal deliverysystems having collagens are described in Example 2.

[0062] In the disclosure below, several therapeutic, prophylactic andcosmetic applications are provided.

[0063] Therapeutic, Prophylactic, and Cosmetic Applications

[0064] Many embodiments are suitable for treatment of subjects either asa preventive measure (e.g., to avoid pain or skin disorders) or as atherapeutic to treat subjects already afflicted with skin disorders orwho are suffering pain. In one embodiment, a method of treatment orprevention of inflammation, pain, or human diseases, such as cancer,arthritis, and Alzheimer's disease, comprises using a transdermaldelivery system of the invention. Because delivery agents such asNSAIDs, capsaicin, and Boswellin interfere and/or inhibit cyclooxygenaseenzymes (COX-1 and COX-2), they will provide a therapeuticallybeneficial treatment for cancer and Alzheimer's disease whenadministered by a transdermal delivery system of the invention. (U.S.Pat. No. 5,840,746 to Ducharme et al., and U.S. Pat. No. 5,861,268 toTang et al.).

[0065] By one approach, a transdermal delivery system comprising adelivery agent that is effective at reducing pain or inflammation (e.g.,NSAIDS, capsaicin, Boswellin, or any combination thereof) isadministered to a subject in need and the reduction in pain orinflammation is monitored. An additional approach involves identifying asubject in need of a COX enzyme inhibitor (e.g., a subject sufferingfrom cancer or Alzheimer's disease) and administering a transdermaldelivery system comprising a delivery agent that inhibits a COX enzyme(e.g., NSAIDS, capsaicin, Boswellin, or any combination thereof).Although many individuals can be at risk for contracting cancer orAlzheimer's disease, those with a family history or a genetic markerassociated with these maladies are preferably identified. Severaldiagnostic approaches to identify persons at risk of developing thesediseases have been reported. (See e.g., U.S. Pat. Nos., 5,891,857;5,744,368; 5,891,651; 5,837,853; and 5,571,671). The transdermaldelivery system is preferably applied to the skin at a region ofinflammation or an area associated with pain or the particular conditionand treatment is continued for a sufficient time to reduce inflammation,pain, or inhibit the progress of the disease. Typically, pain andinflammation will be reduced in 5-20 minutes after application. Cancerand Alzheimer's disease can be inhibited or prevented with prolongeduse.

[0066] In another method of the invention, an approach to reducewrinkles and increase skin tightness and flexibility (collectivelyreferred to as “restoring skin tone”) is provided. Accordingly, atransdermal delivery system comprising a form of collagen as a deliveryagent is provided and contacted with the skin of a subject in need oftreatment. By one approach, a subject in need of skin tone restorationis identified, a transdermal delivery system comprising collagen isadministered to the subject, and the restoration of the skin tone ismonitored. Identification of a person in need of skin restoration can bebased solely on visible inspection and the desire to have tight, smooth,and flexible skin. Treatment with the delivery system is continued untila desired skin tone is achieved. Typically a change in skin tone will bevisibly apparent in 15 days but prolonged use may be required to retainskin tightness and flexibility. The form of collagen in the deliveryagent can be from various sources and can have many different molecularweights, as detailed above. Preferably, high molecular weight collagensare used.

[0067] The transdermal delivery systems of this invention can beprocessed in accordance with conventional pharmacological andcosmetological methods to produce medicinal agents and cosmetics foradministration to patients, e.g., mammals including humans. Thetransdermal delivery systems described herein can be incorporated into apharmaceutical or cosmetic product with or without modification. Thecompositions of the invention can be employed in admixture withconventional excipients, e.g., pharmaceutically acceptable organic orinorganic carrier substances suitable for topical application that donot deleteriously react with the molecules that assemble the deliverysystem. The preparations can be sterilized and if desired mixed withauxiliary agents, e.g., lubricants, preservatives, stabilizers,coloring, aromatic substances and the like that do not deleteriouslyreact with the active compounds. They can also be combined where desiredwith other active agents.

[0068] The effective dose and method of administration of a carriersystem formulation can vary based on the individual patient and thestage of the disease, as well as other factors known to those of skillin the art. Although several doses of delivery agents have beenindicated above, the therapeutic efficacy and toxicity of such compoundsin a delivery system of the invention can be determined by standardpharmaceutical or cosmetological procedures with experimental animals,e.g., ED50 (the dose therapeutically effective in 50% of the population)and LD50 (the dose lethal to 50% of the population). The dose ratio oftoxic to therapeutic effects is the therapeutic index, and it can beexpressed as the ratio, LD50/ED50. Pharmaceutical and cosmetologicalcompositions that exhibit large therapeutic indices are preferred. Thedata obtained from animal studies is used in formulating a range ofdosages for human use. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED50 withlittle or no toxicity. The dosage varies within this range dependingupon the dosage form employed, sensitivity of the patient, and the routeof administration.

[0069] The exact dosage is chosen by the individual physician in view ofthe patient to be treated. Dosage and administration are adjusted toprovide sufficient levels of the active moiety or to maintain thedesired effect. Additional factors that may be taken into accountinclude the severity of the disease state, age, weight and gender of thepatient; diet, time and frequency of administration, drugcombination(s), reaction sensitivities, and tolerance/response totherapy. Short acting compositions are administered daily whereas longacting pharmaceutical compositions are administered every 2, 3 to 4days, every week, or once every two weeks. Depending on half-life andclearance rate of the particular formulation, the pharmaceuticalcompositions of the invention are administered once, twice, three, four,five, six, seven, eight, nine, ten or more times per day.

[0070] Routes of administration of the delivery systems of the inventionare primarily topical, although it is desired to administer someembodiments to cells that reside in deep skin layers. Topicaladministration is accomplished via a topically applied cream, gel,rinse, etc. containing a delivery system of the invention. Compositionsof delivery system-containing compounds suitable for topical applicationinclude, but are not limited to, physiologically acceptable ointments,creams, rinses, and gels.

[0071] In some embodiments, the mixture of penetration enhancer, aqueousadjuvant, and delivery agent is incorporated into a device thatfacilitates application. These apparatus generally have a vessel joinedto an applicator, wherein a transdermal delivery system of the inventionis incorporated in the vessel. Some devices, for example, facilitatedelivery by encouraging vaporization of the mixture. These apparatushave a transdermal delivery system of the invention incorporated in avessel that is joined to an applicator such as a sprayer (e.g., apump-driven sprayer). These embodiments can also comprise a propellantfor driving the incorporated transdermal delivery system out of thevessel. Other apparatus can be designed to allow for a more focusedapplication. A device that facilitates a focused application of atransdermal delivery system of the invention can have a roll-on orswab-like applicator joined to the vessel that houses the transdermaldelivery system. Several devices that facilitate the administration of adelivery system of the invention have a wide range of cosmetic ortherapeutic applications.

[0072] In the example below a clinical study is described that wasperformed to evaluate the efficacy of a transdermal delivery system thatadministered a low molecular weight pain relief solution comprisingcapsaicin.

EXAMPLE 1

[0073] In this example, evidence is provided that a transdermal deliverysystem of the invention can administer a therapeutically effectiveamount of a low molecular weight delivery agent (e.g., 0.225% oleoresincapsicum). A clinical study was performed to evaluate the effectivenessof a transdermal delivery system of the invention comprising 0.225%capsaicin (“EPRS”) as compared to a commercially available creamcomprising Boswellin, 10% methyl salicylate, and 0.25% capsaicin.(Nature's Herbs). The two pain relief preparations were tested on sixsubjects who suffer from degenerative arthritis, debilitating back pain,and/ or bursitis. For the first five days of the study, the subjectsapplied the commercially available cream three times a day. On day six,application of the commercially available cream was stopped and subjectsapplied the EPRS transdermal delivery system. The EPRS pain reliefsolution was also applied for five days, three times a day. Dailyanalysis of the efficacy of the particular pain relief formulations wastaken by the subjects and observations such as the time ofadministration, odor, and therapeutic benefit were recorded after eachadministration.

[0074] The five day use of the commercially available cream was found toprovide only minimal therapeutic benefit. The cream was reported toirritate the skin, have a noxious smell, and provide little decrease inpain or increase in flexibility or range of motion. In contrast, thefive day use of EPRS was reported to provide significant pain relief,relative to the relief obtained from the oral consumption of NSAIDs.Further, EPRS was reported to increase flexibility and range of motionwithin five to twenty minutes after application. Additionally, EPRS didnot present a significant odor nor did it cause skin irritation. Theresults of this study demonstrate that a delivery system comprising alow molecular weight compound, capsaicin, can effectively administer thedelivery agent to cells of the body where it provides therapeuticbenefit.

[0075] In the example below, a clinical study is described that wasperformed to evaluate the efficacy of a transdermal delivery system thatadministered low and high molecular weight collagens.

EXAMPLE 2

[0076] In this example, evidence is provided that a transdermal deliverysystem of the invention can administer a therapeutically effectiveamount of a low and high molecular weight delivery agent (e.g., a lowand high molecular weight collagen). A clinical study was performed toevaluate the effectiveness of several transdermal delivery systems ofthe invention comprising various penetration enhancers, aqueousadjuvants, and collagen delivery agents. The various transdermaldelivery systems that were evaluated are provided in Table 3. Of theformulations that were originally screened, three were extensivelyevaluated by ten subjects (three men and seven women) in a single blindstudy. The formulations analyzed in the single blind study are indicatedin Table 3 by a dagger. That is, the three different formulations (“P1”,“P2”, and “F4”) were evaluated.

[0077] The PI formulation comprised approximately 0.73% to 1.46%Solu-Coll, a soluble collagen having a molecular weight of 300,000daltons. The P2 formulation comprised approximately 1.43% to 2.86%Plantsol, a plant collagen obtained from yeast having a molecular weightof 500,000 daltons. The F4 formulation comprised approximately 11.0% ofHydroColl EN-55, a hydrolyzed collagen having a molecular weight of2,000 daltons. The evaluation of the P1, P2, and F4 formulations was asfollows. Left, right, and center mug-shot photographs were taken with aPentax camera having a zoom 60×lens and Kodak-Gold 100 film beforebeginning the study. Shortly after, each subject was given a bottlehaving a formulation of transdermal delivery system and was instructedto apply the solution to the right side of the face and neck, leavingthe left side untreated, twice daily for 15 days. The F4 formulation wastested first and the application was carried out after showering orwashing and before application of any other product to the treated areaof the face. After the 15 day period, three mug-shot photographs wereagain taken, the subjects recorded their observations on theeffectiveness of the formulation in a questionnaire, and a 7 day periodwithout application of a collagen product provided. The questionnairerequested the subject to assign a score (e.g., a numerical value thatrepresents effectiveness) on characteristics of the transdermal deliverysystem formulation. Characteristics that were evaluated includedtackiness, odor, marketability, and overall effectiveness of theformulation, as well as, whether the formulation tightened the skin,decreased lines, conditioned or softened the skin, and had any negativeside-effects. The scale for the scoring was 1-10, with 1 being the worstrating and 10 being the best rating.

[0078] Following the test of F4, the evaluation detailed above wasconducted on the P1 formulation. Again, photographs were taken beforeand after the second 15 day protocol, a questionnaire evaluating theefficacy of the particular formulation was completed, and a 7 day periodwithout application of a collagen product was provided. Further, afterthe test of P1, the same evaluation was conducted on the P2 formulation,photographs were taken before and after the trial, and a questionnaireevaluating the efficacy of the particular formulation was completed.

[0079] The data from the three evaluation questionnaires were pooled,analyzed using a “t-table” and standard deviation calculations weremade. See Table 4. An overall rating for each particular formulation wasassigned. A perfect score by this system was a 7.875 overall rating. P1was found to have a 4.25 overall rating (approximately 54% effective),P2 was found to have a 4.625 overall rating (approximately 59%effective), and F4 was found to have a 5.625 overall rating(approximately 71% effective).

[0080] The before and after treatment photographs also revealed that thethree tested transdermal delivery systems provided therapeutic benefit.A decrease in wrinkles was observed and an increase in skin tightnessand firmness can be seen. That is, P1, P2, and F4 all providedtherapeutic and/or cosmetic benefit in that they restored skin tone inthe subjects tested. The results presented above also demonstrate thattransdermal delivery systems of the invention can be used to administerhigh molecular weight delivery agents. TABLE 3 ECO Aloe IPA PlantsolEN-55 Solu-coll DMPX YYO Score ID 29.7%* 50.0%* 5.0%* 0* 8.3%* 0*  0* 0* 2 F-1 10.4% 79.0% 5.3% 0 8.7% 0 0 0 3 F-2 5.2% 63.0% 5.3% 0 17.4% 00 0 3 F-3 5.0% 70.0% 5.0% 0 11.0% 0 0 0  3+ F-4 † 4.5% 18.2% 4.6% 0 00.7% to 0 0  3+ P-1 † 1.5% 8.3% 8.3% 8.3% 0.7% to 4.6% 0.3% to 0 0 2Y-500 1.4% 0.7% 0.7% 22.2% 11.1% 1.3% to 0 0 0 0  3+ P-501 2.7% 0.4%35.7% 3.6% 1.1% to 0 0 0 0 2 P-502 2.1% 0.9% 8.7% 0 0 0 2.3% to 0 0 1SC-1 4.6% 1.8% 18.5% 0 0 44.8% 0 0 0  3+ SC-2 1.8% 17.9% 7.1% 0 43.2% 00 0 3 SC-3 0.9% 9.4% 4.7% 0 34.3% 0.3% to 0 0 1 PSCEN 0.6% 1.8% 31.3%6.3% 1.3% to 0 0 0 0  3+ P-1A 2.5% 0.8% 19.2% 3.8% 1.5% to 0 0 7.7% 0.3%5 P-1C 3.1% 0.7% 17.9% 7.1% 1.4% to 0 0 1.1% 0.3% 5 P-2 † 2.9% 0.7%22.2% 11.1% 1.3% to 0 0 0 0  3+ P-501 2.7%

[0081] TABLE 4 Collagen T-Table standard Formulations P1 P2 F4 deviationTackiness 5 3 10 2.94 Skin tightness 7 5 8 1.25 Odor 2 8 8 2.83 Decreaselines 2 2 1 0.47 Soften skin 8 7 4 1.7 Total skin 5 5 6 0.47 restorationMarket Buying 5 7 8 1.25 Power Side effects 0 0 0 0 Total Score 4.254.63 5.63 1.36 (Average)

[0082] Several in vitro techniques are now widely used to assess thepercutaneous absorption of delivery agents. (See e.g., Bronaugh andCollier in In vitro Percutaneous absorption studies:Principle,Fundamentals, and Apiplications, eds. Bronaugh and Maibach, Boca Raton,Fla., CRC Press, pp237-241 (1991) and Nelson et al.,J. Invest. Dermatol.874-879 (1991), herein incorporated by reference). Absorption rates, andskin metabolism can be studied in viable skin without the interferencefrom systemic metabolic processes. In the example below, severalapproaches are described that can be used to evaluate the administrationof a delivery agent by using a transdermal delivery system of theinvention.

EXAMPLE 3

[0083] Skin barrier function can be analyzed by examining the diffusionof fluorescent and colored proteins and dextrans of various molecularweights (“markers”) across the skin of nude mice or swine. Swine skin ispreferred for many studies because it is inexpensive, can be maintainedat −20° C., and responds similarly to human skin. Prior to use, frozenswine skin is thawed, hair is removed, and subcutaneous adipose tissueis dissected away. Preferably, a thickness of skin that resembles thethickness of human skin is obtained (e.g., several millimeters) so as toprepare a membrane that accurately reflects the thickness of the barrierlayer. A dermatome can be pushed across the surface of the skin so as toremove any residual dermis and prepare a skin preparation thataccurately reflects human skin. Elevation of temperature can also beused to loosen the bond between the dermis and the epidermis of hairlessskin. Accordingly, the excised skin is placed on a hot plate or inheated water for 2 minutes at a temperature of approximately 50° C.-60°C. and the dermis is removed by blunt dissection. Chemical approaches(e.g., 2M salt solutions) have also been used to separate the dermisfrom the epidermis of young rodents.

[0084] Many different buffers or receptor fluids can be used to studythe transdermal delivery of delivery agents across excised skin preparedas described above. Preferably, the buffer is isotonic, for example anormal saline solution or an isotonic buffered solution. Morephysiological buffers, which contain reagents that can be metabolized bythe skin, can also be used. (See e.g., Collier et al., Toxicol. Appl.Pharmacol. 99:522-533 (1989)).

[0085] Several different markers with molecular weight from 1,000daltons to 2,000,000 daltons are commercially available and can be usedto analyze the transdermal delivery systems of the invention. Forexample, different colored protein markers having a wide range ofmolecular weights (6,500 to 205,000 daltons) and FITC conjugated proteinmarkers (e.g., FITC conjugated markers from 6,500 to 205,000 daltons)are available from Sigma (C3437, M0163, G7279, A2065, A2190, C1311,T9416, L8151, and A2315). Further, high molecular weight FITC conjugateddextrans (e.g., 250,000, 500,000, and 2,000,000 daltons) are obtainablefrom Sigma. (FD250S, FD500S, and FD2000S).

[0086] Accordingly, in one approach, swine skin preparations, obtainedas described above, are treated with a delivery system lacking adelivery agent and control swine skin preparations are treated withwater. Subsequently, the skin is contacted with a lmM solution of amarker with a known molecular weight suspended in Ringer's solution (pH7.4) at 37° C. After one hour, the skin is frozen and sliced at athickness of 5: m. The sections are counter stained with 5 μg/mlpropidium iodide and, if the marker is FITC conjugated, the sections areanalyzed by fluoresence microscopy. If the marker is a colored marker,diffusion of the marker can be determined by light microscope. Themarker will be retained in the upper layers of the stratum corneum inthe untreated mice but the delivery system treated mice will be found tohave the dye distributed throughout the stratum corneum and any dermallayer that remains.

[0087] Additionally, modifications of the experiments described abovecan be performed by using a delivery system comprising various molecularweight markers. Accordingly, skin preparations are treated with thedelivery system comprising one or more markers and control skinpreparations are treated with water. After one hour, the skin is frozenand sliced at a thickness of 5 μm. The sections can be counter stainedwith 5 μg/ml propidium iodide and can be analyzed by fluoresencemicroscopy (e.g., when a fluorescent marker is used) or alternatively,the sections are analyzed under a light microscope. The various markerswill be retained in the upper layers of the stratum corneum in theuntreated mice but the delivery system treated mice will be found tohave the marker distributed throughout the stratum corneum and anydermal layer that remains.

[0088] In another method, the transdermal water loss (TEWL) ofpenetration enhancer-treated skin preparations can be compared to thatof untreated skin preparations. Accordingly, skin preparations areobtained, as described above, and are treated with a delivery system ofthe invention lacking a delivery agent (e.g., a penetration enhancer).Control skin preparations are untreated. To assess TEWL, an evaporimeteris used to analyze the skin preparation. The Courage and KhazakaTewameter TM210, an open chamber system with two humidity andtemperature sensors, can be used to measure the water evaporationgradient at the surface of the skin. The parameters for calibrating theinstrument and use of the instrument is described in Barel and ClarysSkin Pharmacol. 8: 186-195 (1995) and the manufacturer's instructions.In the controls, TEWL will be low. In contrast, TEWL in penetrationenhancer-treated skin preparations will be significantly greater.

[0089] Further, skin barrier finction can be analyzed by examining thepercutaneous absorption of labeled markers (e.g., radiolabeled,fluorescently labeled, or colored) across skin preparations in adiffusion chamber. Delivery systems of the invention having variousmolecular weight markers, for example, the proteins and dextransdescribed above, are administered to swine skin preparations. Swine skinpreparations are mounted in side-by-side diffusion chambers and areallowed to stabilize at 37° C. with various formulations of penetrationenhancer. Donor and receiver fluid volumes are 1.5ml. After 1 hour ofincubation, a labeled marker is added to the epidermal donor fluid toyield a final concentration that reflects an amount that would beapplied to the skin in an embodiment of the invention. Five hundred:1 ofreceiver fluid is removed at various time points, an equal volume ofpenetration enhancer is added to the system. The aliquot of receiverfluid removed is then analyzed for the presence of the labeled marker(e.g., fluorescent detection, spectroscopy, or scintillation counting).Control swine skin preparations are equilibrated in Ringer's solution(pH 7.4) at 37° C.; the same concentration of labeled marker as used inthe experimental group is applied to the donor fluid after one hour ofequilibration; and 500 μl of receiver fluid is analyzed for the presenceof the marker. In the experimental group, the steady-state flux oflabeled marker in the skin will be significantly greater than that ofthe control group.

[0090] By using these approaches, several transdermal delivery systemscan be evaluated for their ability to transport low and high molecularweight delivery agents across the skin.

[0091] Although the invention has been described with reference toembodiments and examples, it should be understood that variousmodifications can be made without departing from the spirit of theinvention. Accordingly, the invention is limited only by the followingclaims. All references cited herein are hereby expressly incorporated byreference.

What is claimed is:
 1. A transdermal delivery system comprising anethoxylated oil and a delivery agent.
 2. The transdermal delivery systemof claim 1, further comprising water.
 3. The transdermal delivery systemof claim 1, further comprising an alcohol.
 4. The transdermal deliverysystem of claim 1, wherein said ethoxylated oil comprises an animal oilor a vegetable oil.
 5. The transdermal delivery system of claim 1,wherein said ethoxylated oil comprises an oil selected from the groupconsisting of castor oil, jojoba oil, corn oil, and emu oil.
 6. Thetransdermal delivery system of claim 1, wherein said delivery agent is anon-steroidal anti inflammatory drug (NSAID).
 7. The transdermaldelivery system of claim 1, wherein said non-steroidal anti inflammatorydrug (NSAID) is selected from the group consisting of ibuprofen(2-(isobutylphenyl)-propionic acid); methotrexate (N-[4-(2, 4 diamino6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid); aspirin(acetylsalicylic acid); salicylic acid; diphenhydramine(2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen(2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (−));phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione);sulindac-(2)-5-fuoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene-]-1H-indene-3-aceticacid; diflunisal (2′,4′, -difluoro-4-hydroxy-3-biphenylcarboxylic acid;piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-2-carboxamide 1, 1-dioxide, an oxicam; indomethacin(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-H-indole-3-acetic acid);meclofenamate sodium (N-(2, 6-dichloro-m-tolyl) anthranilic acid, sodiumsalt, monohydrate); ketoprofen (2-(3-benzoylphenyl)-propionic acid;tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl-1H-pyrrole-2-acetatedihydrate); diclofenac sodium (2-[(2,6-dichlorophenyl)amino] benzeneaticacid, monosodium salt); hydroxychloroquine sulphate(2-{[4-[(7-chloro-4-quinolyl) amino]pentyl]ethylamino}ethanol sulfate(1:1); penicillamine (3-mercapto-D-valine); flurbiprofen([1,1-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (+−.)); cetodolac(1-8-diethyl-13,4,9, tetra hydropyrano-[3-4-13] indole-1-acetic acid;mefenamic acid (N-(2,3-xylyl)anthranilic acid; and diphenhydraminehydrochloride (2-diphenyl methoxy-N, N-di-methylethamine hydrochloride).8. The transdermal delivery system of claim 1, wherein the deliveryagent is a protein or fragment thereof.
 9. The transdermal deliverysystem of claim 8, wherein the delivery agent is a collagen.
 10. Thetransdermal delivery system of claim 8, wherein the delivery agent hasan approximate average molecular weight of less than or equal to 1,000daltons.
 11. The transdermal delivery system of claim 9, wherein thecollagen has an approximate average molecular weight from about 2,000daltons to about 500,000 daltons.
 12. The transdermal delivery system ofclaim 9, wherein the collagen has an approximate average molecularweight of about 2,000 daltons and the therapeutically effective amountby weight or volume is 0.1% to 50.0%.
 13. The transdermal deliverysystem of claim 9, wherein the collagen has an approximate averagemolecular weight of about 300,000 daltons and the therapeuticallyeffective amount is 0.1% to 2.0%.
 14. The transdermal delivery system ofclaim 9, wherein the collagen has an approximate average molecularweight of about 500,000 daltons and the therapeutically effective amountby weight or volume is 0.1% to 4.0%.
 15. A method of reducing pain orinflammation comprising: identifying a subject in need of a reduction inpain or inflammation; and providing said subject a transdermal deliverysystem according to claim
 1. 16. The method of claim 15, wherein saidtransdermal delivery system further comprises water.
 17. The method ofclaim 15, wherein said transdermal delivery system further comprises analcohol.
 18. The method of claim 15, wherein said ethoxylated oilcomprises an animal oil or a vegetable oil.
 19. The method of claim 15,wherein said ethoxylated oil comprises an oil selected from the groupconsisting of castor oil, jojoba oil, corn oil, and emu oil.
 20. Themethod of claim 15, wherein said delivery agent is a non-steroidal antiinflammatory drug (NSAID).
 21. The method of claim 15, wherein saidnon-steroidal anti inflammatory drug (NSAID) is selected from the groupconsisting of ibuprofen (2-(isobutylphenyl)-propionic acid);methotrexate (N-[4-(2, 4 diamino6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid); aspirin(acetylsalicylic acid); salicylic acid; diphenhydramine(2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen(2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (−));phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione);sulindac-(2)-5-fuoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene-]-1H-indene-3-aceticacid; diflunisal (2′,4′, -difluoro-4-hydroxy-3-biphenylcarboxylic acid;piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-2-carboxamide 1, 1-dioxide, an oxicam; indomethacin(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-H-indole-3-acetic acid);meclofenamate sodium (N-(2, 6-dichloro-m-tolyl) anthranilic acid, sodiumsalt, monohydrate); ketoprofen (2-(3-benzoylphenyl)-propionic acid;tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl-1H-pyrrole-2-acetatedihydrate); diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneaticacid, monosodium salt); hydroxychloroquine sulphate(2-{[4-[(7-chloro-4-quinolyl) amino]pentyl]ethylamino}ethanol sulfate(1:1); penicillamine (3-mercapto-D-valine); flurbiprofen([1,1-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (+−.)); cetodolac(1-8- diethyl-13,4,9, tetra hydropyrano-[3-4-13] indole-1-acetic acid;mefenamic acid (N-(2,3-xylyl)anthranilic acid; and diphenhydraminehydrochloride (2-diphenyl methoxy-N, N-di-methylethamine hydrochloride).22. A method of treating or preventing cancer and Alzheimer's diseasecomprising the step of identifying a subject in need of a COX enzymeinhibitor and administering to said subject a transdermal deliverysystem according to claim
 20. 23. A method of treating or preventingcancer and Alzheimer's disease comprising the step of identifying asubject in need of a COX enzyme inhibitor and administering to saidsubject a transdermal delivery system according to claim
 21. 24. Amethod of reducing wrinkles in the skin comprising: identifying asubject in need of skin tone restoration; and providing to said subjecta transdermal delivery system according to claim
 1. 25. The method ofclaim 24, wherein said delivery system further comprises water.
 26. Themethod of claim 24, wherein said delivery system further comprises analcohol.
 27. The method of claim 24, wherein said ethoxylated oilcomprises an animal oil or a vegetable oil.
 28. The method of claim 24,wherein said ethoxylated oil. comprises an oil selected from the groupconsisting of castor oil, jojoba oil, corn oil, and emu oil.
 29. Themethod of claim 24, wherein said delivery agent is a protein or fragmentthereof.
 30. The method of claim 29, wherein the delivery agent has anapproximate average molecular weight of less than or equal to 1,000daltons.
 31. The method of claim 29, wherein the delivery agent is acollagen.
 32. The method of claim 31, wherein said collagen has anapproximate average molecular weight from about 2,000 daltons to about500,000 daltons.
 33. The method of claim 31, wherein said collagen hasan approximate average molecular weight of about 2,000 daltons.
 34. Themethod of claim 31, wherein said collagen has an approximate averagemolecular weight of about 300,000 daltons and the therapeuticallyeffective amount is 0.1% to 2.0%.
 35. The method of claim 31, whereinsaid collagen has an approximate average molecular weight of about500,000 daltons and the therapeutically effective amount by weight orvolume is 0.1% to 4.0%.